Penicillamine

Last updated

Penicillamine
Penicillamine structure.svg
D-penicillamine-from-xtal-3D-bs-17.png
Clinical data
Trade names Cuprimine, Cuprenyl, Depen, others
Other names
  • D-penicillamine
  • (–)-penicillamine
AHFS/Drugs.com Monograph
MedlinePlus a618021
License data
Pregnancy
category
  • AU:D
Routes of
administration
By mouth (capsules)
ATC code
Legal status
Legal status
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability Variable
Metabolism Liver
Elimination half-life 1 hour
Excretion Kidney
Identifiers
  • (2S)-2-amino-3-methyl-3-sulfanylbutanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.136 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C5H11NO2S
Molar mass 149.21 g·mol−1
3D model (JSmol)
  • CC(C)([C@H](C(=O)O)N)S
  • InChI=1S/C5H11NO2S/c1-5(2,9)3(6)4(7)8/h3,9H,6H2,1-2H3,(H,7,8)/t3-/m0/s1 Yes check.svgY
  • Key:VVNCNSJFMMFHPL-VKHMYHEASA-N Yes check.svgY
   (verify)

Penicillamine, sold under the brand name of Cuprimine among others, is a medication primarily used for the treatment of Wilson's disease. [1] It is also used for people with kidney stones who have high urine cystine levels, rheumatoid arthritis, and various heavy metal poisonings. [1] [2] It is taken by mouth. [2]

Contents

Penicillamine was approved for medical use in the United States in 1970. [1] It is on the World Health Organization's List of Essential Medicines. [3]

Medical uses

It is used as a chelating agent:

In cystinuria, a hereditary disorder in which high urine cystine levels lead to the formation of cystine stones, penicillamine binds with cysteine to yield a mixed disulfide which is more soluble than cystine. [7]

Penicillamine has been used to treat scleroderma. [8]

Penicillamine can be used as a disease-modifying antirheumatic drug (DMARD) to treat severe active rheumatoid arthritis in patients who have failed to respond to an adequate trial of conventional therapy, [9] although it is rarely used today due to availability of TNF inhibitors and other agents, such as tocilizumab and tofacitinib. Penicillamine works by reducing numbers of T-lymphocytes, inhibiting macrophage function, decreasing IL-1, decreasing rheumatoid factor, and preventing collagen from cross-linking.

Adverse effects

Common side effects include rash, loss of appetite, nausea, diarrhea, and low blood white blood cell levels. [1] Other serious side effects include liver problems, obliterative bronchiolitis, and myasthenia gravis. [1] It is not recommended in people with lupus erythematosus. [2] Use during pregnancy may result in harm to the baby. [2] Penicillamine works by binding heavy metals; the resulting penicillamine–metal complexes are then removed from the body in the urine. [1]

Bone marrow suppression, dysgeusia, anorexia, vomiting, and diarrhea are the most common side effects, occurring in ~20–30% of the patients treated with penicillamine. [10] [11]

Other possible adverse effects include:

Chemistry

D-Penicillamine.svg
D-(–)-(S)-Penicillamine
(antiarthritic)
L-Penicillamine.svg
L-(+)-(R)-Penicillamine
(toxic)

Penicillamine is a trifunctional organic compound, consisting of a thiol, an amine, and a carboxylic acid. It is an amino acid structurally similar to cysteine, but with geminal dimethyl substituents α to the thiol. Like most amino acids, it is a colorless solid that exists in the zwitterionic form at physiological pH.

Penicillamine is a chiral drug with one stereogenic center; the two enantiomers have distinctly different physiological effects. (S)-penicillamine (D-penicillamine, having (–) optical rotation) is antiarthritic. [18] (R)-penicillamine (L-penicillamine, having (+) optical rotation) is toxic because it inhibits the action of pyridoxine (also known as vitamin B6). [19] That enantiomer is a metabolite of penicillin but has no antibiotic properties itself. [20] A variety of penicillamine–copper complex structures are known. [21]

History

John Walshe first described the use of penicillamine in Wilson's disease in 1956. [22] He had discovered the compound in the urine of patients (including himself) who had taken penicillin, and experimentally confirmed that it increased urinary copper excretion by chelation. He had initial difficulty convincing several world experts of the time (Denny-Brown and Cumings) of its efficacy, as they held that Wilson's disease was not primarily a problem of copper homeostasis but of amino acid metabolism, and that dimercaprol should be used as a chelator. Later studies confirmed both the copper-centered theory and the efficacy of D-penicillamine. Walshe also pioneered other chelators in Wilson's such as triethylene tetramine and tetrathiomolybdate. [23]

Penicillamine was first synthesized by John Cornforth under supervision of Robert Robinson. [24]

Penicillamine has been used in rheumatoid arthritis since the first successful case in 1964. [25]

Cost

In the United States, Valeant raised the cost of the medication from about US$500 to US$24,000 per month in 2016. [26]

Related Research Articles

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<span class="mw-page-title-main">Rheumatoid arthritis</span> Type of autoimmune arthritis

Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involved, with the same joints typically involved on both sides of the body. The disease may also affect other parts of the body, including skin, eyes, lungs, heart, nerves, and blood. This may result in a low red blood cell count, inflammation around the lungs, and inflammation around the heart. Fever and low energy may also be present. Often, symptoms come on gradually over weeks to months.

<span class="mw-page-title-main">Wilson's disease</span> Genetic multisystem copper-transport disease

Wilson's disease is a genetic disorder characterized by the excess build-up of copper in the body. Symptoms are typically related to the brain and liver. Liver-related symptoms include vomiting, weakness, fluid build-up in the abdomen, swelling of the legs, yellowish skin, and itchiness. Brain-related symptoms include tremors, muscle stiffness, trouble in speaking, personality changes, anxiety, and psychosis.

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References

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